This invention relates to compounds for inhibiting the binding of fibrinogen to blood platelets, and for inhibiting the aggregation of blood platelets.
Fibrinogen is a glycoprotein, present in blood plasma, which participates in platelet aggregation and fibrin formation. Platelets are cell-like anucleated fragments, found in the blood of all mammals, which participate in blood coagulation. Interaction of fibrinogen with a receptor on the platelet membrane glycoprotein complex IIb/IIIa is known to be essential for normal platelet function. Zimmerman et al., U.S. Pat. No. 4,683,291, describes peptides having utility in the study of fibrinogen-platelet, platelet-platelet, and cell-cell interactions. The peptides are described as having utility where it is desirable to retard or prevent formation of a thrombus or clot in the blood. The general formula for the peptides is: EQU H.sub.2 N-(Ch)-Arg-Gly-Asp-(Cx)-H
where Ch and Cx are sequences of amino acids.
Pierschbacher et al., U.S. Pat. No. 4,589,881, describes the sequence of an 11.5 kDal polypeptide fragment of fibronectin which embodies the cell-attachment-promoting activity of fibronectin. A specifically described fragment is: ##STR2## Ruoslahti et al., U.S. Pat. No. 4,614.517, describes tetrapeptides which alter cell-attachment activity of cells to various substrates. The peptides are stated to "consist essentially of" the following sequence: EQU X-Arg-Gly-Asp-Ser-Y
wherein X is H or one or more amino acids and Y is OH or one or amino acids. FIG. 1 lists the polypeptides that were synthesized by Ruoslahti et al. in "determining the smallest peptide exhibiting cell attachment activity".
Ruoslahti et al., U.S. Pat. No. 4,578,079, describes similar tetrapeptides having Ser substituted with Thr or Cys. PA0 Pierschbacher et al., Proc. Natl. Acad..Sci. USA, Vol. 81, pp.5985-5988, October 1984 describe variants of the cell recognition site of fibronectin that retain attachment-promoting activity. They assayed the cell attachment-promoting activities of a number of structures closely resembling the Arg-Gly-Asp-Ser peptide, and found "that the arginine, glycine, and aspartate residues cannot be replaced even with closely related amino acids, but that several amino acids can replace serine without loss of activity." PA0 Ruoslahti et al., Science, Vol. 238, pp. 491-497, Oct. 23, 1987, discuss cell adhesion proteins. They specifically state that "[e]lucidation of the amino acid sequence of the cell-attachment domain in fibronectin and its duplication with synthetic peptides establish the sequence Arg-Gly-Asp (RGD) as the essential structure recognized by cells in fibronectin". PA0 Cheresh, Proc. Natl. Acad. Sci. USA, Vol. 84, pp. 6471-6475, September 1987, describes the Arg-Gly-Asp-directed adhesion receptor involved in attachment to fibrinogen and von Willebrand Factor. PA0 Adams et al., U.S. Pat. No. 4,857,508, describes tetrapeptides which inhibit platelet aggregation and the formation of a thrombus. The tetrapeptides have the formula: EQU X-Gly-Asp-Y PA0 XX shares an amide bond with Gly and an amide bond with ZZ, and is defined as having a side chain X ##STR5## wherein: n is 1,2,3 or 4; PA0 Preferably, when X is defined by (i), then n+n' is 3, AA is a single bond and R is phenyl or benzyl. PA0 Preferably, when X is defined by (ii), then n+n' is 5, AA is a single bond and R is H. PA0 ZZ is defined as follows: ##STR6## wherein: A' is H, acylamido, acylaminoacylamido, acylamino-N-methylamino-acylamido;
wherein X can be H2NC(.dbd.NH)NH(CH2)nCH(Z)COOH or Ac-Arg, wherein Z.dbd.H, NH2, or NH-Acyl and n=1-4, and wherein Y can be Tyr-NH2, Phe-NH2 or a group of a specifically defined formula.
Applicants have discovered fibrinogen receptor antagonists which do not contain the amino acid sequence Arg-Gly-Asp which is taught in the art as specifically required for binding to platelet membrane glycoprotein complex IIb/IIIa.